NSAIDs significantly reduce the incidence and risk of death from colorectal cancer, but their long-term use for chemoprevention is not recommended because of potentially fatal side-effects resulting from cyclooxygenase (COX) inhibition and the suppression of physiological prostaglandins. Some investigators have concluded that the mechanism for the anticancer activity of NSAIDs may not require COX inhibition, but involves selective apoptosis induction of neoplastic cells and suggest that safer and more efficacious non-COX inhibitory derivatives can be developed by targeting the underlying pathway leading to apoptosis. We have extensively studied the mechanism by which the NSAID sulindac induces apoptosis and reported that this activity is closely associated with its ability to inhibit cyclic guanosine monophosphate phosphodiesterase (cGMP PDE), which activates cGMP/protein kinase G signaling to suppress oncogenic -catenin/Tcf-mediated transcriptional activity and the synthesis of key cell cycle regulatory proteins, such as cyclin D1 and survivin. We recently discovered that PDE10 is a critically important target of sulindac, which is elevated in colon tumors and essential for tumor cell growth. Using the indene scaffold of sulindac, we synthesized a series of non-COX inhibitory derivatives that selectively inhibit PDE10 and tumor cell growth. A prototype inhibitor, MCI-020 was identified with strong antitumor activity and the potential to inhibit metastasis. Further chemical optimization of MCI-020 and studies to better define the role of PDE10 in colorectal tumorigenesis are, however, necessary to develop this approach for chemoprevention. The following aims are proposed: 1) design and synthesize novel sulindac derivatives with selectivity to inhibit PDE10, 2) evaluate PDE10 selectivity and in vitro anticancer activity of sulindac derivatives, 3) determine in vivo anticancer activity of promising sulindac derivatives in mouse models of colon tumor growth and metastasis, and 4) measure PDE10 expression during colon tumorigenesis in whole animals and human clinical samples. The goal is to identify a lead compound with safety and efficacy attributes that will merit consideration for clinical trials. Elucidation of the role of PDE10 in colorectal tumorigeness may also provide insight to biomarkers and imaging methods for the early detection of cancer using radiopharmaceuticals.